Researchers at Yale-New Haven have a long history of taking on giants
in the realm of disease: fatal bacterial infections, heart failure, sick
or premature newborns and diabetes are just a few of the areas where Yale
doctors have been responsible for dramatic advances in medicine.

Today, Yale clinicians and researchers are building upon their long
history of research into nerve repair and transplantation to aggressively
wage war against multiple sclerosis (MS) and related diseases. One recently
completed clinical trial tested the effect of oral interferon on patients
with MS. Another ongoing trial is examining the use of the cholesterol-lowering
drug, simvastatin. But, perhaps the most exciting project of all, involving
cell transplantation in humans, has attracted international attention and
doctors and patients around the world are awaiting its outcome.

Only July 18 and 19 [2001], a team of Yale-New Haven neurologists and
a neurosurgeon performed surgery at Yale-New Haven Hospital on a 53-year-old
patient with an advanced form of MS. If the procedure proves effective
and safe, they will have made a dramatic advance in the quest to repair
the central nervous system of MS patients.

When Nerves Don't Communicate Well

MS affects as many as 350,000 Americans, two-thirds women, who as a
result experience problems with muscle control and strength, vision, balance
and sensation. In MS, recurring inflammation in the brain and spinal cord-the
central nervous system-damages the "fatty" or lipid coating (myelin) that
surrounds and insulates nerve fibers (called demyelination).

Myelin allows the conduction of impulses from one part of the body to
another. It can be destroyed in acquired diseases such as multiple sclerosis
and by hereditary metabolic disorders such as the leukodystrophies. A scar
forms where myelin is destroyed, which disrupts impulses produced by the
nervous system. These scars or lesions can occur randomly in a person's
nervous system, but prove more disabling when they occur in the spinal
cord or brainstem.

While MS is rarely life-threatening, its impact on a person ranges from
mild to severely disabling.

What Could Be a Medical Milestone

In that Yale-New Haven operating room in July, YNHH neurosurgeon Dennis
Spencer, M.D., transplanted myelin-forming Schwann cells into the central
nervous system of a woman with a serious form of MS. Before surgery, Jeffrey
Kocsis, Ph.D., professor of neurology and neurobiology, had already supervised
preparation of the Schwann cells taken from the patient's own peripheral
nerves, specifically the sural nerve. The cells were prepared for transplant
in the Frisbee III Laboratory, a Class 10,000 clean room suitable for delicate
manipulations of cells. The cells were isolated overnight and delivered
on ice to the operating room ready for the surgery.

During surgery, these Schwann cells were transplanted into the right
frontal lobe of the patient's brain using stereotactic technology that
enables the surgeon to be extremely precise in positioning the transplanted
cells. According to Dr. Kocsis, Schwann cells are implanted because they
are generally considered safe for transplantation.

If the cells behave in humans as they have in animal studies, they will
replace the damaged cells and begin to re-coat, or remyelinate, nerves
in the brain and spinal cord. Dr. Timothy Vollmer, YNHH neurologist and
associate professor of neurology at Yale School of Medicine, is the study's
principal investigator. He points out that the current study, while groundbreaking
and receiving much international attention, is really the progression of
the school's long history of research into neurological repair and nerve
transplantation.

It All Begins in the Lab

Research involving humans is never begun without a tremendous amount
of basic research in the laboratory. And between basic science discoveries
and improved patient care lies a gulf that many universities and companies
struggle to bridge.

"This research project stands out, not only for what we are trying to
accomplish, but also for the fact that our team of neuroscientists, clinicians,
neurosurgeon, imaging experts, Frisbee Lab staff and a great support staff
worked so effectively together to bridge that gap," said Dr. Vollmer.

In a series of experiments involving rats, Dr. Kocsis had already proven
that enough Schwann cells could be extracted for transplantation, that
transplanted cells could lead to remyelination of MS-type lesions and that
impulse conduction improved in the transplanted nerves of the rats.

Based on this research and a resulting paper, a protocol for research
conducted in humans was developed that attracted the attention of The Myelin
Project based in Washington, D.C. While some earlier studies in neural
cell transplantation in Parkinson's disease had been disappointing, the
Yale team felt that the controls in these earlier studies had been weak.
They would correct for that in their own study.

Funding Research

The Myelin Project was the logical organization to be interested in
this type of research. The Project limits its funding to clinically oriented
experiments on the cutting edge of remyelination research. The organization
represents a multinational group of families whose lives have been affected
by demyelinating diseases. Its stated purpose is to accelerate research
on myelin repair by "giving scientists adequate, prompt financing and by
continuously interacting with them."

The project was founded by Augusto and Michaela Odone, whose son Lorenzo
is afflicted with an inherited demyelinating disease, adrenoleukodystrophy.
Their story was dramatized in a 1992 movie, "Lorenzo's Oil."

Drawing upon the expertise of the world's top laboratories engaged in
myelin repair, The Project has formed a work group that includes researchers
from Mount Sinai Medical Center, the Istituto Superiore di Sanitá
in Rome, the Collège de France, the University of Wisconsin at Madison,
the Hopital de la Salpêtrière and the Institut Pasteur in
Paris, the Queen's University at Kingston in Canada, the University of
Cambridge in the UK, and the Max-Planck Institut in Germany. Researchers
at Yale had an opportunity to discuss their protocol and receive input
with other members of the work group.

The Yale Protocol
Every element of the protocol, or the procedure for how this research
would be conducted, was carefully designed to guard the patient's safety,
while producing meaningful results. "We're taking a very conservative approach,"
said Dr. Kocsis. "We are transplanting a small number of cells using minimal
surgery." Doctors chose the right frontal lobe of the brain because it
is the safest area of the central nervous system for the patient to undergo
this type of transplant surgery, as well as an easier area to monitor.

Schwann cells taken from the patient herself, rather than a donor, reduced
the risk of rejection. And because MS does not attack Schwann cells and
the myelin they produce, they are likely to better withstand any future
attack from the disease. In January 2002, a biopsy of tissue at the site
of the implant will be examined to determine the following:

Did the cells taken from the peripheral nerves survive long term?

If they survived, did the transplanted cells produce myelin?

If they produced myelin, how much did they make?

If the procedure proves promising and is determined to be safe, an additional
four MS patients will undergo the procedure over the next 12 to 18 months.
The next two patients are scheduled to undergo surgery in March or April
2002, at which time more Schwann cells will be transplanted than were transplanted
into the first patient. In this second phase of the study, researchers
will again monitor how well the transplanted cells survive, but they'll
also measure the number of fibers remyelinated. The goal would be to remyelinate
at least 20 to 40 percent of the fibers in a one- to two-cubic centimeter
lesion.

Watch and Wait

If nerve impulse conductivity is improved in humans thanks to the transplanted
cells, researchers are optimistic this may lead at some point to an improvement
in function. However, functional improvements are not being measured by
the current clinical study-which is engaged in what researchers refer to
as proof of concept.

"If we can show even modest remyelination," said research associate
Jana Preiningerova, M.D., the project manager, "then we can proceed to
the next phase of clinical studies and see if transplantation of Schwann
cells into critically located lesions may bring back some function to our
patients."

While they await the biopsy that will prove or disprove their theory,
doctors monitor the patient closely and follow her progress via MRI scans
of the brain and clinical examinations. Currently, no complications have
been encountered and the patient is doing well. Only time will tell.

If the outcome is encouraging, this trial represents a small-but very
significant step-along the road to finding a cure or more effective treatment
for the disease whose cause is still unknown.

"If it works," concluded Dr. Vollmer, "it may be a model of how to test
other cell types and will encourage new studies."